Increased blood vessel receptor protein expression found in female mice may explain differences in MS incidence rates between women and men
MS is a disease with a strong sex bias, with women being up to four times more likely to be affected than men. The reasons for this difference remain unclear; however, researchers have indicated genetic, hormonal and environmental contributions. A study that was recently conducted at the Washington University School of Medicine in St. Louis, Missouri may be able to provide more insight into this issue and future therapeutic strategies.
Dr. Lillian Cruz-Orengo and colleagues looked at a strain of mice that exhibits MS-like characteristics in order to investigate the sex difference in MS incidence. By examining DNA segments from female and male mice, they were able to investigate levels of proteins in the central nervous system (CNS), composed of the brain and spinal cord, to determine if there are any significant differences between genders. The team also looked at postmortem human CNS tissue from 20 subjects, of which 10 had MS and 10 did not.
DNA analysis revealed differences in activation of up to 20 genes in the CNS of female mice versus male mice. One of the genes, which codes for a blood vessel protein called S1PR2, was found at higher levels in female mice. This increase was also found in areas of the CNS that are more susceptible to MS. The follow-up with the postmortem brain tissue supported the findings in mice, with the highest levels of S1PR2 being found in two females with relapse-remitting MS. The researchers discovered that S1PR2 has an important role because it regulates which cells can travel through the blood-brain barrier (BBB). By treating the mice with an agent that blocks S1PR2, researchers were able to lessen the MS disease.
This is the first study which identifies sexual differences in structures of the brain which may explain why females are more vulnerable to developing MS than males. Researchers suggest that increased levels of S1PR2 in disease-susceptible regions of the CNS of females may lead to increased numbers of immune cells entering the CNS and causing inflammation.
In addition to providing clues about gender differences in MS incidence, results from this study offer implications for the development of treatments for relapsing-remitting MS. Drugs that target S1PR2, specifically by decreasing its activity or expression, may help to limit the entry of cells that lead to inflammation of the CNS. Currently there is a MS drug called Gilenya that is available to the public and targets other proteins that are in the same family as S1PR2. Further research will be required in order to validate these study findings and lead to the development of a drug that can target S1PR2.
Cruz-Orengo L et al. Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmune susceptibility. The Journal of Clinical Investigation 2014 May 8 [Epub ahead of print].